Understanding the mechanism of a nematode molecular Achilles' heel.

寄生虫是对人类健康和全球粮食安全的重大挑战。这些动物的影响因耐药、因环境问题而取消现有治疗以及寄生虫因气候变化和人类迁徙而扩展到新环境而加剧。因此，迫切需要开发新的控制方法。开发新疗法的理想目标将是仅在线虫中发现的分子和过程，而在它们感染的动物和植物中不存在。理想情况下，这些靶点可以在所有线虫中找到，从而开发出一种有效对抗多种线虫感染的药物。其中一个过程是剪接前导反式剪接，这是许多线虫基因变得活跃的重要步骤。我们已经证明，两个“分子机器”需要剪接前导反式剪接。这些机器不起作用的线虫会停止发育并不育。然而，我们还没有了解这些机器的详细知识，无法了解它们是如何运作的，而这是正确开发抑制它们的药物的必要前提。特别是，我们不知道所有的组成部分，我们不了解那些我们知道的。为了应对这些挑战，我们正在实验线虫秀丽隐杆线虫中系统地研究这些机器的组成部分。到目前为止，我们的工作已经确定了一种新的成分，它具有使其成为理想的潜在药物靶点的特性。拟议的研究将扩展我们的初步研究，以提供一个全面的分子机制，支持线虫基因表达的这一重要步骤。在不同的生物群体中，剪接前导反式剪接的过程已经进化了多次，其中许多也是重要的寄生虫。因此，除了允许开发潜在的治疗线虫感染的新药外，我们的发现将作为研究其他“版本”反式剪接之间的异同的起点。

Parasitic nematodes are major challenges to human health and global food security. The impact of these animals is exacerbated by drug resistance, withdrawal of existing treatments due to environmental concerns, and expansion of parasites into new environments through climate change and human migration. There is thus an urgent need to develop new control methods. Ideal targets for the development of new therapeutics would be molecules and processes that are found only in nematodes and are absent from the animals and plants that they infect. Ideally these targets would be found in all nematodes, enabling the development of a drug active against a broad range of nematode infections. One such process is spliced leader trans-splicing, which is an essential step by which many nematode genes become active.We have shown that two 'molecular machines' are required for spliced leader trans-splicing. Nematodes in which these machines are non-functional stop developing and are infertile. However, we don't have the detailed knowledge of these machines needed to understand how they function, a necessary precondition to properly develop drugs that inhibit them. In particular, we don't know all the components involved, and we don't understand those that we do know about. To address these challenges, we are systematically studying the components of these machines in the experimental nematode Caenorhabditis elegans. Our work so far has led to the identification of a new component which has properties that make it an ideal potential drug target. The proposed research will extend our initial studies, to give a comprehensive picture of the molecular machinery that underpins this essential step in nematode gene expression. The process of spliced leader trans-splicing has evolved multiple times in different groups of organisms, many of which are also important parasites. Thus, as well as allowing the development of potential new drugs to treat nematode infections, our findings will serve as a starting point to investigate the similarities and differences between other 'versions' of trans-splicing.